title: Prostate cancer stem cell-targeted efficacy of a new-generation taxoid, SBT-1214 and novel polyenolic zinc-binding curcuminoid, CMC2.24.
abstract: BACKGROUND
  Prostate cancer is the second leading cause of cancer death among men. Multiple evidence suggests that a population of tumor-initiating, or cancer stem cells (CSCs) is responsible for cancer development and exceptional drug resistance, representing a highly important therapeutic target. The present study evaluated CSC-specific alterations induced by new-generation taxoid SBT-1214 and a novel polyenolic zinc-binding curcuminoid, CMC2.24, in prostate CSCs.
  
  
  RESULTS
  The CD133(high)/CD44(high) phenotype was isolated from spontaneously immortalized patient-derived PPT2 cells and highly metastatic PC3MM2 cells. Weekly treatment of the NOD/SCID mice bearing PPT2- and PC3MM3-induced tumors with the SBT-1214 led to dramatic suppression of tumor growth. Four of six PPT2 and 3 of 6 PC3MM2 tumors have shown the absence of viable cells in residual tumors. In vitro, SBT-1214 (100 nM-1 µM; for 72 hr) induced about 60% cell death in CD133(high)/CD44(+/high) cells cultured on collagen I in stem cell medium (in contrast, the same doses of paclitaxel increased proliferation of these cells). The cytotoxic effects were increased when SBT-1214 was combined with the CMC2.24. A stem cell-specific PCR array assay revealed that this drug combination mediated massive inhibition of multiple constitutively up-regulated stem cell-related genes, including key pluripotency transcription factors. Importantly, this drug combination induced expression of p21 and p53, which were absent in CD133(high)/CD44(high) cells. Viable cells that survived this treatment regimen were no longer able to induce secondary spheroids, exhibited significant morphological abnormalities and died in 2-5 days.
  
  
  CONCLUSIONS
  We report here that the SBT-1214 alone, or in combination with CMC2.24, possesses significant activity against prostate CD133(high)/CD44(+/high) tumor-initiating cells. This drug combination efficiently inhibits expression of the majority of stem cell-related genes and pluripotency transcription factors. In addition, it induces a previously absent expression of p21 and p53 ("gene wake-up"), which can potentially reverse drug resistance by increasing sensitivity to anti-cancer drugs.
authors.affiliation: Department of Pathology, Stony Brook University Medical Center, Stony Brook, New York, United States of America ; Institute of Chemical Biology & Drug Development, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Galina I
authors.initials: GI
authors.lastname: Botchkina
authors.forename: Edison S
authors.initials: ES
authors.lastname: Zuniga
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Rowehl
authors.forename: Rosa
authors.initials: R
authors.lastname: Park
authors.forename: Rahuldev
authors.initials: R
authors.lastname: Bhalla
authors.forename: Agnieszka B
authors.initials: AB
authors.lastname: Bialkowska
authors.forename: Francis
authors.initials: F
authors.lastname: Johnson
authors.forename: Lorne M
authors.initials: LM
authors.lastname: Golub
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Shroyer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D043823:Taxoids / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000589611:1,7-bis(4-hydroxyphenyl)-4-N-phenylaminocarbonylhepta-1,6-dien-3,5-dione; D000970:Antineoplastic Agents; C101719:SB T-1214; D043823:Taxoids; D003474:Curcumin